PROSTATE CANCER

IJPCBS 2013, 3(1), 185-199
Lalla et al.
ISSN: 2249-9504
INTERNATIONAL JOURNAL OF PHARMACEUTICAL, CHEMICAL AND BIOLOGICAL SCIENCES
Review Article
Available online at www.ijpcbs.com
PROSTATE CANCER
JK. Lalla*, Sunita Ogale2, Vikram Gota3 Meena Shah4 and Deven Parmar5
Sanskruti, 20 / 701-702, Thakur Complex, Kandivli (E), Mumbai, Maharashtra, India.
INTRODUCTION
The two Articles published earlier by us
were number one is on general cancer
&second is on breast cancer. In continuation
with this, we would like to emphasis on
prostate cancer here.
secreted into prostatic fluid and semen,
small amounts of PSA are present in
blood.[See fig. no. 1 which depict the
Anatomy of Prostate gland]
Anatomy, Physiology &Pathophysiology
ofProstate gland1,1a
The prostate gland is present only in males,
although females have homologous glands
(having the same embryological origin)
around the urethra; these are called
'Skene's glands' or 'the female prostate'.
The prostate gland surrounds the proximal
part of the urethra as it exits the base of the
bladder.The size of the prostate varies with
age ranging from size of a walnut, but it can
be much larger in older men.It produces
fluid that protects and nourishes sperm
cells in semen, making the semen fluid.
Semen is a gray and rather opalescent,
turbid fluid having pH of 7.2 to 8.0.Life &
movement of sperms depends on important
properties of semen.A groove down the
centreof the prostate gland divides it into
left and right lobes.
Anatomists more precisely describe the
prostate gland as having anterior, posterior,
lateral, and median lobes, whereas
pathologists sometimes describe the
prostate as having zones (peripheral,
central, transitional, periurethral, and
fibromuscular). The peripheral zone
accounts for most of the prostate gland and
about 75% of prostate cancers.
Fluid secreted by the prostate forms about
30% of the volume of semen.
PSA is a protein produced by normal and
cancerous prostate cells.
PSA is secreted by prostate epithelial cells
into prostatic fluid, where its function is to
liquefy semen and thus allow spermatozoa
to move more freely. Although PSA is
Fig. 1: Anatomy of prostate gland© 2009
WebMD, LLC.
Several types of cells are found in the
prostate, but almost all prostate cancers
developfrom the glandularcells. Glandular
cells make the prostate fluid that is added to
the semen. The medical term for a cancer
that starts in glandular cells is
adenocarcinoma.
Other types of cancer can also start in the
prostate gland, including sarcomas, small
cellcarcinomas, and transitional cell
carcinomas. But these types of prostate
cancer are sorare that if you have prostate
cancer it is almost certain to be an
adenocarcinoma.
Some prostate cancers can grow and spread
quickly, but most grow slowly. In
fact,autopsy studies show that many older
men (and even some younger men) who
died ofother diseases also had prostate
cancer that never affected themduring their
lives. Inmany cases neither they nor their
doctors even knew they had it.
Microscopic Anatomy
Historically, the prostate has been divided
into 3 zones: (1) transition zone, (2) central
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zone, and (3) peripheral zone. The
transition zone accounts for 10% of the
prostatic glandular tissue and 20% of the
adenocarcinomas.The prostate consists of
approximately 70% glandular tissue and
30% fibromuscularstroma.
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where 70% of adenocarcinomas are found.
This area is also the location most
commonly affected by chronic prostatitis.
Possible pre-cancerous conditions of the
prostate
Prostate cancer maystarts out as a following
pre-cancerous condition,
Transition zone
The prostatic urethra courses the length of
the prostate from the level of the bladder
neck to the level of the membranous
urethra. The epithelium consists of
transitional cells similar to bladder
epithelium. This transitional zone is where
benign prostatic hyperplasia occurs and can
lead to bladder outlet obstruction when an
adenoma grows to a significant size. When
the adenoma grows large enough, it can
compress
the
fibromuscular
band
surrounding this zone, creating a surgical
capsule.
The transitional zone is often described as
having 2 lateral lobes and a median lobe
that lead to the symptoms of the lower
urinary tract symptoms. A urethral crest
runs along the posterior midline and
disappears at the membranous urethra. On
both sides of the urethral crest, there is a
grove where the prostatic sinuses exist and
drain all of the glandular elements.
The urethral crest widens and protrudes
from the posterior wall as the seminal
colliculus (verumontanum). A small midline
pit, the prostatic utricle, is found at the apex
of the seminal colliculus. On either side of
the utricular orifice, the small slitlike
openings to the ejaculatory duct can be
found.
Prostatic intraepithelial neoplasia (PIN)
In this condition, there are changes in how
the prostate gland cells look under
themicroscope, but the abnormal cells don't
look like they are growing into other parts
of theprostate (like cancer cells would).
Based on how abnormal the patterns of
cells look, they are classified as:
[a] Low-grade PIN: the patterns of prostate
cells appear almost normal.
[b] High-grade PIN:the patterns of cells look
more abnormal.
Proliferative
inflammatory
atrophy
(PIA)
This is another finding that may be noted on
a prostate biopsy.In PIA, the prostate
cellslook smaller than normal, and there are
signs of inflammation in the area. PIA is
notcancer, but researchers believe that PIA
may sometimes lead to high-grade PIN,
orperhaps to prostate cancer directly.[See
fig. no. 2]
Changes taking place during the prostate
cancer are depicted in Figure 2
Central zone
The central zone is the area surrounding the
ejaculatory ducts. This zone consists of 25%
of the glandular tissue. Very few
adenocarcinomas are found in this region
and can represent as little as 1-5% of these
tumors in the prostate.
http://www.elsevierimages.com/images/vt
n/000/000/027/27881-150x150.jpg
Fig. 2: Proliferative inflammatory atrophy
(PIA) as a precursor to prostatic
intraepithelial neoplasia (PIN) and prostate
cancer. (Adapted from Nelson WG, DeMarzo
Peripheral zone
The peripheral zone of the prostate
constitutes 70% of the glandular tissue.
This zone covers the posterior and lateral
aspects of the prostate. The peripheral zone
is the area that is palpated on digital rectal
examination (DRE) and represents the area
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AM, Isaacs WB: Prostate cancer. N Engl J
Med 2003;349:366–381.)
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of prostate cancer by increasing folate
levels for the cancer cells to use to survive
and grow; PSMA increases available folates
for use by hydrolyzing glutamated-folates.
Pathophysiology of prostate cancer 2
Prostate cancer is classified as an
adenocarcinoma, or glandular cancer, that
begins when normal semen-secreting
prostate gland cells mutate into cancer cells.
The region of prostate gland where the
adenocarcinoma is most common is the
peripheral zone. Initially, small clumps of
cancer cellsremain confined to otherwise
normal prostate glands, a condition known
as carcinoma in situ or prostatic
intraepithelial neoplasia (PIN). Although
there is no proof that PIN is a cancer
precursor, it is closely associated with
cancer. Over time, these cancer cells begin
to multiply and spread to the surrounding
prostate tissue (the stroma) forming a
tumor. Eventually, the tumor may grow
large enough to invade nearby organs such
as the seminal vesicles or the rectum, or the
tumor cells may develop the ability to travel
in the bloodstream and lymphatic system.
Prostate cancer is considered a malignant
tumor because it is a mass of cells that can
invade other parts of the body. This
invasion of other organs is called
metastasis. Prostate cancer most commonly
metastasizes to the bones, lymph nodes,
rectum, and bladder. The prostate is a zinc
accumulating, citrate producing organ. The
protein ZIP1 is responsible for the active
transport of zinc into prostate cells. One of
zinc's important roles is to change the
metabolism of the cell in order to produce
citrate, an important component of semen.
The process of zinc accumulation, alteration
of metabolism, and citrate production is
energy inefficient, and prostate cells
sacrifice enormous amounts of energy
(ATP) in order to accomplish this task.
Prostate cancer cells are generally devoid of
zinc. This allows prostate cancer cells to
save energy not making citrate, and utilize
the new abundance of energy to grow and
spread. The androgen receptor helps
prostate cancer cells to survive and is a
target for many anti cancer research
studies; so far, inhibiting the androgen
receptor has only proven to be effective in
mouse studies. Prostate specific membrane
antigen (PSMA) stimulates the development
IMPORTANCE OF AWARENESS3
Although there is growing awareness about
women-affecting cancers like cervical and
breast cancer, male-centric tumours are
usually given step-motherly treatment.
Despite the high-incidence of prostate
cancer
among men in the age group of 55-60 years
in united states, there is no documented
data to understand its prevalence in india.
As men aged over 50 years are at high risk
from the disease, it is advisable for anyone
over that age to undergo check-up as the
disease is easier to cure,if detected early. To
spread awareness about the disease, free
prostate cancer awareness camp shall be
organized by government & nongovernment organizations.
Early diagnosis is the key to beat prostate
cancer. Educational programs can increase
the awareness and use of cancer screening.
PROSTATE CANCER STATISTICS IN
INDIA4
Prostate cancer incidence is increasing in
India by 1% every year. The average age
adjusted incidence rates for prostate cancer
in Indian registries are ranged from
4.1/100,000 for Chennai registry to
8.1/100,000 for Delhi registry, incidence
rate of 6.3/100,000 at Mumbai registry and
at Bangalore registry it is 5.6/100,000 in
2002-03.
Cancer Registries are under the network of
National Cancer Registry Programme
(NCRP) of Indian Council of Medical
Research (ICMR), New Delhi. The Cancer
Registry has been collecting all essential
data pertaining to cancer patients, in the
resident population of the respective areas.
The registry collects information, analyzes
it, and produces a report which is presented
to the Indian Council of Medical
Research.This report presents information
like number of cancer cases registered,
cancer rate in men, women and children,
number of deaths registered due to cancer,
common cancer site in men, common cancer
site is women etc which in turn helps to
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plan the various prevention, awareness,
curative programs.
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Recently, some common gene variations
have been linked to a higher risk of prostate
cancer.
IMPORTANCE OF PROSTATE CANCER ON
BASIS OF GLOBAL STATISTICS5
More than 241,000 men will be diagnosed
with prostate cancer in 2012 and 28,170
will die from the disease,in USA according
to an estimate by the National Cancer
Institute.
1 in 6 men will be diagnosed with prostate
cancer.1 in 10,000 under age 40 will be
diagnosed, the rate shoots up to 1 in 39 for
ages 40 to 59, and 1 in 14 for ages 60 to 69.
In fact, about 65% of all prostate cancers
are diagnosed in men over the age of 65.
Diet-There appears to be a link with people
living in urban areas exposed to pollution
and those consuming large quantities of
dietary fat. Lower blood levels of vitamin D
may increase the risk of developing prostate
cancer.
Obesity- Some studies have found that
obese men have a lower risk of getting a
low-grade (lessdangerous) form of the
disease, but a higher risk of getting more
aggressive prostate cancer.
RISKFACTORS6
Age-Although men of any age can get
prostate cancer,age is the strongest risk
factor. Over 80% of prostate cancer
diagnoses occurring in men older than age
65 years. The degree to which the incidence
of prostate cancer increases exponentially
with age is greater than with any other
cancer. Autopsy studies found that as many
as 75% of men older than age 85 years have
prostate cancer at the time of death.
Inflammation of the prostate- Some
studies have suggested that prostatitis
(inflammation of the prostate gland) may
belinked to an increased risk of prostate
cancer; Inflammation is often seen in
samples of prostate tissue that also contain
cancer. Thelink between the two is not yet
clear, but this is an active area of research.
Sexually
transmitted
infectionsResearchers have looked to see if sexually
transmitted infections (like gonorrhea,
orchlamydia) might increase the risk of
prostate cancer, possibly by leading
toinflammation of the prostate.
Family history- Having a first-degree
relative with a history of prostate cancer
increases the risk two- to three-fold.
However; the exact genes responsible for
the development of prostate cancer are not
known.
Vasectomy- Some earlier studies had
suggested that men who have had a
vasectomy (minor surgery tomake men
infertile) – especially those younger than 35
at the time of the procedure – mayhave a
slightly increased risk for prostate cancer.
But most recent studies have not foundany
increased risk among men who have had
this operation.
Ethnic/racial
backgroundAfricanAmerican men are 1.6 times more likely to
develop prostate cancer compared with
Caucasian men, and are nearly 2.4 times as
likely to die from the disease. It is rare
among the Chinese.
Other potential risk factors- The
endogenous levels of androgens and other
hormones (vitamin D levels, insulin-like
growth
factors),
inflammation,
and
vasectomy status may also be associated
with prostate cancer risk.
PROGNOSIS7
Prostate cancer rates are higher in
developed countries than in the rest of the
world. Many of the risk factors for prostate
cancer are more prevalent in the developed
world, including longer life expectancy and
diets high in red meat.Also, where there is
more access to screening programs, there is
a higher detection rate. Prostate cancer is
the ninth-most-common cancer in the
world, but is the number-one non-skin
Genes- Scientists have found few inherited
gene changes that seem to raise prostate
cancerrisk, but they account for a very small
percentage of prostate cancer cases.
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cancer in men from the United States.In
India in the 1990s, half of the people with
prostate cancer confined to the prostate
died within ten years.African-American men
have 50–60 times more prostate cancer and
prostate cancer deaths than men in
Shanghai,China&Nigeria.In patients who
undergo treatment, the most important
clinical prognostic indicators of disease
outcome are stage, pre-therapy PSA level,
and Gleason score. In general, the higher the
grade and the stage, the poorer the
prognosis.
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studied further to see how quickly the
cancer will spread.
This measure is known as the Gleason
score. The lower the score, the less likely
the cancer will spread.
 A Gleason score of 6 or less means the
cancer is unlikely to spread.
 A Gleason score of 7 means that there is
a moderate chance of the cancer
spreading. If the biopsy shows the
presence of cancer, patient may need
more tests to see if the cancer has
spread.
 Imaging
tests
-computerized
tomography
(CT)
or
magnetic
resonance imaging (MRI) scans may
pinpointthe location of cancer that has
spread beyond the prostate.
 Bone scans and x-rays -- these tests look
for spread of cancer to the bones.
 Lymph node biopsy -- a surgical
procedure to find out if the cancer has
spread to the lymphatic system.
DETECTION AND DIAGNOSIS8,8a
There is no single test to diagnose prostate
cancer. The main tests include:
 A urine test to rule out a urine infection
 Digital rectal exam (DRE) -- in this test,
the doctor inserts a gloved, lubricated
finger into the rectum in order to feel
the prostate for bumps or other
abnormalities. Many malignant tumors
begin in the outer part of the prostate
and may be found with this exam. Some
men find this test embarrassing, but it is
quick,relatively painless, and helps find
many prostate cancers.
 PSA test -- a blood test measuring the
level of prostate-specific antigen (PSA).
Prostate cancer cells produce higher
amounts of PSA, so measuring PSA
levels may help find cancer while it is
still microscopic. However, finding
elevated levels of PSA does not always
mean that a man has cancer. Benign
conditions such as an enlarged prostate
can also elevate PSA levels.If either the
DRE or PSA test suggests that cancer
might be present, doctor may
recommend the followingtests:
 Transrectal ultrasound -- using a small
probe inserted into the rectum, sound
waves help get a visual imageof the
prostate.
 Biopsy of the prostate -- a tissue sample
is obtained through the rectum and
examined for cancerous cells.
Stages of Prostate Cancer
The clinical stage of cancer is important in
choosing a treatment. The clinical stage tells
how much the cancer may have grown
within the prostate and whether it has
spread to other tissues or organs. In case of
surgery, lymph nodes, and seminal vesicles
nearby prostate will be removed and
samples of them studied under a
microscope. This exam gives the pathologist
the information to find out the pathological
stage toone’s cancer. Based on this doctor
may do one or more of the following tests or
exams to help figure out the stage of cancer:
 DRE
 Prostate biopsy
 Bone scan
 MRI
 CT scan
 Biopsy of the lymph nodes in the pelvis
 Biopsy of the seminal vesicles
Tumor Stages
Prostate cancer is typically staged according
to the American Joint Committee on
Cancer’s tumour, node, metastasis (TNM)
system, in which the tumour stage (T) is
based on the extent of penetration or
invasion beyond the prostatic capsule into
adjacent structures (Table 1). Localized
Gleason score
The samples of tissue from the biopsy are
then studied in microscopically. If
cancerous cells are found, they can be
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prostate cancer is classified as stages T1
(non-palpable) and T2 (palpable) and is
confined within the prostatic capsule. The
likelihood of progression to invasive cancer
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is associated with the presence of more
poorly differentiated cells and other
histopathologic features.
Table 1: Showing Prostate Cancer Tumor Staging*
Tumor
Stage
TX
T0
Description
Primary tumor cannot be assessed
No evidence of primary tumor
Clinically unapparent tumor not palpable or visible by imaging T1a: Tumor incidental
histologic finding in ≤5% of tissue resected T1b: Tumor incidental histologic finding in
T1
>5% of tissue resected T1c: Tumor identified by needle biopsy (e.g., because of elevated
PSA levels)
Tumor confined within prostate T2a: Tumor involves 50% of one lobe or less T2b: Tumor
T2
involves >50% of one lobe but not both lobes T2c: Tumor involves both lobes
Tumor extends through the prostate capsule
T3
T3a: Extracapsular extension (unilateral or bilateral) T3b: Tumor invades seminal
vesicle(s)
Tumor is fixed or invades adjacent structures other than seminal vesicles: bladder neck,
T4
external sphincter, rectum, levator muscles, and/or pelvic wall
* From the American Joint Committee on Cancer.
According to the National Institute of
cancer, T1 means that the cancer is so small
it can’t be felt during a DRE. T1a and T1b
cancer is most often found by accident,
when men have surgery to relieve
symptoms of BPH (benign prostatic
hyperplasia).
T1c is most often found when a prostate
biopsy is done because of a PSA test result
that showed a high PSA blood level. This is
the most commonly diagnosed stage of
prostate cancer.
A stage of T2 means that prostate cancer
can be felt during a DRE, but is still only in
the prostate. The stage may be a, b, or c,
depending on the cancer’s size and whether
it is in 1 or more lobes of the prostate.
Information flows in a cell from
DNA
RNA
Protein. A rearrangement
or translocation of chromosomes results in
two abnormally fused genes whose
abnormal RNA and protein products put
cells on the path to cancer. Such gene
fusions are commonly found in human
cancers such as prostate and leukemia.
Researchers have identified abnormal RNA
fusions that were generated without any
changes to their corresponding genomic
DNA by a mechanism they’ve dubbed “cissplicing of adjacent genes,” or cis-SAGe, for
short.
When analyzing the prostate cancer cell
lines, Dr.Hui Li and his team found fusions
in the RNA products of the SLC45A3 and
ELK4 genes located adjacent to each other
on chromosome 1. They showed that this
SLC45A3-ELK4 RNA fusion transcript was
generated by an aberrant read-through of
the two genes, when the message should
have stopped transcribing after the first
gene. This aberrant read-through was
termed cis-SAGe.Li and his team observed
that SLC45A3-ELK4 fusion RNA promoted
cancer cell growth in vitro and that the
levels of SLC45A3-ELK4 fusion RNA in
human prostate samples correlated with
disease
progression—non-cancerous
prostate tissue had the lowest levels of
SLC45A3-ELK4 fusion RNA; men with
metastatic prostate cancer had the highest.
The new cell lines are the first available
derived from a bone metastasis of an
IN-VITRO DETECTION
Prostate cancer cell lines9.9a
Cell lines are widely used in many aspects of
laboratory research and particularly as in
vitro models in cancer research. They have
number of advantages; for example, they
are easy to handle and represent an
unlimited self-replicating source that can be
grown in almost infinite quantities. They
represent a relatively high degree of
homogeneity and are easily replaced from
frozen stock if lost through contamination.
However cell lines that have been deposited
for long period in banks may prone to
genotypic and phenotypic drift during their
continual culture.
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androgen-independent
prostatic
adenocarcinoma that grow both in vivo and
in vitro and have retained PSA expression
and
androgen
sensitivity.
Scientists
developed a novel cell line which mimics
the stages of resistance to androgen therapy
for study of the molecular mechanisms by
which androgen therapy sensitive prostate
cancer cells differentiate to androgen
resistant cancer cells. This technology will
allow the generation of entirely novel
methods for screening, treatment and
prevention of androgen resistant prostate
cancer. These cell lines are available in
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market and UNeMed currently offers a
variety
of
licensing
options
and
collaborative development opportunities
with the University of Nebraska Medical
Center.
Cell lines are marketed by ---- American
Type Culture Collection [ ATCC], Life
technologies& others.
SIGNS AND SYMPTOM10
Many men with prostate cancer often have
no symptoms. If symptoms appear, they
include:
Table 2: Describes signs & symptoms
Blood in the urine
The need to urinate frequently, especially at night
Weak or interrupted urine flow
Pain or burning feeling while urinating
The inability to urinate
Constant pain in the lower back, pelvis, or upper thighs
Painful ejaculation.
CENTRES FOR DETECTION & DIAGNOSIS
IN INDIA
given certain exams and tests, including
biopsies, on a regular schedule.
Dharamshila Hospital ------------------Delhi
Indian Cancer Society---------------------Mumbai
BGS Global Hospital -----------------------Bangalore
DeenanathMangeshkar Hospital & Res.
Centre ------------------------ Pune
Chemotherapy
Chemotherapy is a cancer treatment that
uses drugs to stop the growth of cancer
cells, either by killing
the cells or by stopping them from dividing.
When chemotherapy is taken by mouth or
injected into a vein
or muscle, the drugs enter the bloodstream
and can reach cancer cells throughout the
body (systemic
chemotherapy). When chemotherapy is
placed directly into the cerebrospinal fluid,
an organ, or a body
cavity such as the abdomen, the drugs
mainly affect cancer cells in those areas
(regional chemotherapy).
TYPES OF TREATMENT11,11a
Different types of treatment are available
for patients with prostate cancer. Some
treatments arestandard (the currently used
treatment), and some are being tested in
clinical trials.
Six types of standard treatment are used.
Watchful waiting or active surveillance
Watchful waiting is closely monitoring a
patient’s condition without giving any
treatment until symptoms
appear or change.
Active surveillance is closely following a
patient's condition without giving any
treatment unless there are
changes in test results. It is used to find
early signs that the condition is getting
worse. In active surveillance, patients are
Biologic therapy
Biologic therapy is a treatment that uses the
patient’s immune system to fight cancer.
Substances made
by the body or made in a laboratory are
used to boost, direct, or restore the body’s
natural defenses
against cancer. This type of cancer
treatment is also called biotherapy or
immunotherapy. Sipuleucel-T is
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a type of biologic therapy used to treat
prostate cancer that has metastasized
(spread to other parts of the
body).
Hormone Therapy
Male sex hormones, such as testosterone,
can help prostate cancer grow. Hormone
therapy slows prostate cancer’s growth by
reducing the body’s ability to make
testosterone or by blocking testosterone’s
action in prostate cancer cells.
Hormone therapy used in the treatment of
prostate cancer may include the following :
 Luteinizing
hormone-releasing
hormone agonists can prevent the
testicles from making testosterone.
Examples are leuprolide, goserelin, and
buserelin.
 Antiandrogens can block the action of
androgens (hormones that promote
male sex characteristics).Examples are
enzalutamide,
flutamide,
and
nilutamide.
 Drugs that can prevent the adrenal
glands from making androgens include
ketoconazole and aminoglutethimide.
 Orchiectomy is a surgical procedure to
remove one or both testicles, the main
source of male hormones, to decrease
the amount of hormone being made.
 Estrogens (hormones that promote
female sex characteristics) can prevent
the testicles from making testosterone.
However, estrogens are seldom used
today in the treatment of prostate
cancer becauseof the risk of serious side
effects.



Radiation Therapy
This type of treatment uses high doses of
radiation energy to treat cancer. Radiation
therapy is a good choice with early-stage
prostate cancer. It is also the best treatment
for older men or those who have other
health problems. There are different types
of radiation therapy:
 External beam radiation- In this type
of radiation therapy, a machine aims
radiation at cancer.The machine moves
around body, sending radiation from
many directions. The treatment once a
day, 5 days a week, for 6 to 9 weeks may
be given. Each treatment session usually
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lasts
about
15
minutes.
3-D conformal radiation therapy is a
type of external beam radiation that is
often used to treat prostate cancer. It
allows doctors to carefully plan the
shape of the radiation beam so it targets
the cancer more precisely, while
avoiding healthy tissues nearby.
Brachytherapy- is a type of internal
radiation therapy in which a doctor
places radioactive material inside the
prostate. Brachytherapy is a choice for
men with low-risk prostate cancer.
There are two main types of
brachytherapy used for prostate cancer,
low-dose rate (also called LDR) and
high-dose rate (also called HDR).
LDR brachytherapy- In this type of
brachytherapy, a doctor will place lowdose sources of radiation, or seed
implants, throughout your prostate.
Each seed implant is smaller than a
grain of rice. The number of seeds will
depend on the size of your prostate. The
radiation will get weaker each day and
run out in 2 to 10 months.
HDR brachytherapy- Before treatment
starts, a doctor will place tiny catheters
(hollow tubes) throughout prostate. For
each treatment, the doctor will place 1
or more sources of high-dose radiation
in the prostate through the catheters.
Then, radioactive material will be
removed after a few minutes. The
catheters will remain in place for the
entire course of treatment.The catheters
will be removed, once treatment is over.
External beam radiation therapy and
brachytherapy can be used together.
Surgery
Surgery is a treatment choice for men with
early-stage prostate cancer who are in good
health. Surgery to remove the prostate is
called prostatectomy. There are different
types of surgery for prostate cancer. They
include:
 Open prostatectomy. Also called
retropubic prostatectomy. In this
surgery, the prostate is removed
through a single long cut made in
abdomen from a point below navel to
just above the pubic bone. This type of
surgery can be used for nerve-sparing
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surgery. Nerve-sparing surgery lessens
the chances that the nerves near your
prostate will be harmed. These
important nerves control erections and
normal bladder function.
Laparoscopic surgery. In this type of
surgery, uses a laparoscope to see and
remove the prostate. This surgery is
done through 4 to 6 small cuts in the
navel and the abdomen.
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DRUG
DISCOVERY
RESEARCH
&RECENTLY
DISCOVERED
TREATMENTS12,12a,12b,12c
Discovery and development of anticanceragents are the key focus of several
pharmaceutical companies as well as nonprofitgovernment and non-government
organizations, like the National Cancer
Institute (NCI) in the United States, the
European Organization for Researchand
Treatment of Cancer (EORTC), and the
British Cancer Research Campaign(CRC).
The pharmaceutical industry is increasingly
looking for ways to speed development of
new drugs.
The Institute of Cancer Research, London,
and its partner hospital The Royal Marsden
NHS Foundation Trust jointly led the new
Phase III trial of enzalutamide and the
Phase III trials of two other drugs,
cabazitaxel
and
abiraterone.
Drug
enzalutamide can significantly extend life
and improve quality of life in men with
advanced prostate cancer. The drug, Xtandi
(enzalutamide) made by pharmaceutical
companies Medivation and Astellas, could
be licensed for use by British patients early
next year,2013.The US Food and Drug
Administration (FDA) announced that
Xtandi has been approved for men with
metastatic castration-resistant prostate
cancer that has recurred or spread,
regardless of whether patients received
medical or surgical therapy to reduce
testosterone levels.
Progenics Pharmaceuticals Inc. has opened
enrollment in a Phase 2 study in prostate
cancer patients of its PSMA ADC compound.
PSMA ADC is a targeted anti-cancer
therapeutic that uses a monoclonal
antibody to deliver a cell-killing drug to
malignant cells.
According to a report issued by PhRMA
(formerly known as the Pharmaceutical
Research and Manufacturers Association),
there are approximately 80 drugs currently
in clinical development for the treatment of
prostate cancer.
Gamma-Tocotrienol Kills Prostate Cancer
Stem Cells. A study reveals that gammatocotrienol is effective in targeting prostate
cancer stem cells, offering a potential means
to prevent cancer growth and disease
relapse.
Perineal prostatectomy. In this type
the prostate is removed through an
incision between scrotum and anus.
This type of surgery is not used very
often.
New types of treatment are being tested
in clinical trials.
Cryosurgery
Cryosurgery is a treatment that uses an
instrument to freeze and destroy prostate
cancer cells. This type of treatment is also
called cryotherapy.
High-intensity focused ultrasound
High-intensity focused ultrasound is a
treatment that uses ultrasound (highenergy sound waves) to destroy cancer
cells. To treat prostate cancer, an endorectal
probe is used to make the sound waves.
Proton beam radiation therapy
Proton beam radiation therapy is a type of
high-energy, external radiation therapy that
targets tumors with streams of protons
(small, positively charged particles). This
type of radiation therapy is being studied in
the treatment of prostate cancer.
Medication
List of medicines used to treat prostate
cancer and approved by FDA.
Finasteride
Degarelix
Jevtana (Cabazitaxel)
Lupron (Leuprolide Acetate)
Xtandi (Enzalutamide)
Zytiga (Abiraterone Acetate)
Prednisone
Provenge (Sipuleucel-T)
Taxotere (Docetaxel)
Viadur (Leuprolide Acetate)
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Lalla et al.
Scientists from Singapore, Australia and
Hong Kong have found that gammatocotrienol is potent in killing prostate
cancer stem cells. This small group of cells
is responsible for the initiation of prostate
cancer and is resistant to conventional
chemotherapy drugs. It causes relapses in
the cancer by producing new chemoresistant cancer cells. Gamma-tocotrienol is
a member of the Vitamin E family and is
derived naturally from palm oil. This study
aimed to find a way to eradicate prostate
cancer stem cells. It follows an earlier
report that demonstrated the effectiveness
of gamma-tocotrienol in targeting the bulk
of the prostate tumour mass. This latest
finding highlights the considerable potential
of gamma-tocotrienol as a natural remedy
to prevent and treat prostate cancer.
The scientists found that low doses of
gamma-tocotrienol cause apoptosis in the
prostate cancer stem cells and suppress
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their colony formation capability. This
results in a lower prostate cancer stem cell
population (as defined by the protein
markers CD133 and CD44).
Further tests in mice models were
conducted, where mice implanted with
hormonal refractory prostate cancer cells
were given gamma-tocotrienol orally. The
results showed that gamma-tocotrienol not
only reduced tumour size formed, but also
decreased the incidence rate of tumour
formation by 75%, as compared to the
control group of mice, which had 100%
tumour formation. These results strongly
suggest that gamma-tocotrienol could be
developed for prostate cancer prevention
and treatment. "Current chemotherapy
drugs, such as Docetaxel, have limited effect
on prostate cancer stem cells, although they
are currently the first-line drug given to
patients with advanced hormonal refractory
prostate cancer.
Table 3: illustrates products under development by leading pharma companies
Pharmaceutical company
Centocor Ortho Biotech
Novartis Pharmaceuticals
Bristol-Myers Squibb
NewLink Genetics
Johnson & Johnson
Abbott pharmaceuticals
IncuronBuffalo
Molecular Insight
PolyphenonPharma
DendreonSeattle
Amgen
Genta
OncoGenex Pharmaceuticals
AstraZeneca
New molecule
Siltuximab
Imatinib
Ipilimumab
Prostate cancer vaccine
JNJ-26854165
leuprorelin depot (6-month formulation)
mepacrine
MIP1095 and radiolabelled diagnostic
polyphenonE
Sipuleucel-T
Rilotumumab
Tesetaxel
custiren
Zibotentan
New Dosage Forms
Magnetic nanoparticles (MNPs) and
polymer magnetic nanoparticles (PMNPs)
have been attracting a great amount of
attention because of their numerous
applications including contrast agents in
magnetic resonance imaging (MRI),
magnetic targeted drug carriers, and
hyperthermia treatments for cancer.
Researcher have developed the polymer
magnetic nanoparticles (PMNPs) using a
silane coupling agent and a novel thermosensitive polymer, N-isopropylacrylamideacrylamide-allylamine (NIPA-AAm-AH). The
temperature-sensitive
polymers
were
chosen as a shell for the purpose of creating
a controlled drug delivery system. In this
Use
hormone-refractory prostate cancer
prostate cancer
prostate cancer
hormone-refractory prostate cancer
prostate cancer
prostate cancer
hormone-refractory prostate cancer
diagnosis of prostate cancer
prostatic intraepithelialneoplasia
androgen-dependent recurrent prostate cancer
early stage prostate cancer
advanced prostate cancer
prostate cancer
castration-resistant prostate cancer
system, the temperature induced by the
magnetic core would be used to release
therapeutic agents from the polymer shell
at a specific location. The chemical and
physical properties of these PMNPs were
determined using Fourier transformed
infrared spectroscopy, nuclear magnetic
resonance,
x-ray
photoelectron
spectroscopy, and a superconducting
quantum interference device.
COMPLEMENTARY AND ALTERNATIVE
THERAPIES13
These treatment methods are not practiced
by conventional western medicine. They
can include herbal, animal derived, and
mind-body
approaches
to
treating
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IJPCBS 2013, 3(1), 185-199
Lalla et al.
cancer.The scientific evidence about the
efficacy of these treatments either refutes
cancer fighting claims or is inconclusive at
the present time.
Nutrition and Dietary Supplements
A comprehensive treatment plan to support
the health of men living with prostate
cancer may include a range of
complementary and alternative therapies.
Preliminary studies suggest that some
nutritional supplements may reduce the
symptoms of some prostate cancers or
reduce risk of developing it.
Tips to reduce risk of developing prostate
cancer:
 Eat antioxidant foods, including fruits
(such as berries, watermelon, and
tomatoes) and vegetables (such as
squash and bell peppers).
 Include more cruciferous vegetables
(such as broccoli, cauliflower, cabbage,
and Brussels sprouts) in diet. One
preliminary study suggested men who
eat three or more servings a week
reduced their chance of developing
prostate cancer. Another study found
that men who ate 28 or more servings
of all kinds of vegetables per week were
35% less likely to develop prostate
cancer than those who had fewer than
14 servings per week. These foods also
appear to have anticancer properties in
test tube studies.

Some studies show men who regularly
eat fish have a lower risk of prostate
cancer than those who don't eat as
much fish.

High-fat diets may raise risk of prostate
cancer.
 Stay at a proper weight, and exercise
regularly.

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found that lycopene inhibits the growth
of prostate cancer cells in test tubes.
Lycopene also appears to reduce the
risk of developing prostate cancer.
Vitamin E -- in one lab test, a specific
form of vitamin E blocked the growth of
prostate cancer cells. Vitamin E may
also lower the risk of developing
prostate cancer in men who smoke.
Overall, studies on vitamin E and
prostate cancer have been mixed. More
research is needed to know whether
vitamin E is helpful for men who
already have prostate cancer.
Herbs
Herbs are generally a safe way to
strengthen and tone the body's systems.
Individuals may use herbs as dried extracts
(such as capsules, powders, and teas),
glycerites (glycerine extracts), or tinctures
(alcohol extracts). Unless otherwise
indicated, one should make teas with 1 tsp.
herb per cup of hot water. Steep covered 5 10 minutes for leaf or flowers, and 10 - 20
minutes for roots. Drink 2 - 4 cups per day.
 Green
tea
(Camellia
sinensis)
standardized extract, 250 - 500 mg
daily, is an antioxidant that may
decrease risk of cancer and heart
disease. In one study, green tea extract
seemed to have a slight benefit in
treating some forms of prostate cancer.
Use caffeine-free products.
 Saw
palmetto
(Serenoarepens)
standardized extract, 160 mg two times
daily, has been shown in some studies
to help with symptoms of benign
prostatic hyperplasia. It seems to have
anti-androgenic effects. However, it's
not clear whether saw palmetto has any
effect on prostate cancer. And
researchers have been concerned that
saw palmetto could mask prostate
cancer by lowering prostate-specific
antigen (PSA) levels. However, a
randomized study of more than 1,000
patients did not show this effect on PSA
levels.
 Milk thistle (Silybummarianum) -- In
one lab test, milk thistle stopped
prostate cancer cells from growing.
However, there is no evidence yet that it
works in humans.
Following nutrients may have cancerfighting properties
 Lycopene, 15 mg two times per day, is
an antioxidant found in tomatoes and
waterrmelon. In one preliminary study,
men with prostate cancer either
received a lycopene supplement or
placebo for 3 weeks before undergoing
prostate surgery. Those who received
the supplement had less aggressive
growth of cancer cells than those who
received placebo. Lab studies have also
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

Lalla et al.
Pomegranate (Punicagranatum) -- In
one study, men who had surgery or
radiation to treat prostate cancer that
had not spread and who drank 8 oz. of
pomegranate juice every day slowed
down the time it took their PSA levels to
double. Researchers think that meant
that their tumors may have not grown
as fast, either. More research needs to
be done.
Garlic (Allium sativum), standardized
extract, 400 mg two to three times daily,
may help fight cancer cells, but more
research is needed to know whether it's
effective against prostate cancer. Garlic
can interact with many medications. It
may increase the risk of bleeding,
particularly if you also take blood
thinners such as warfarin (Coumadin)
or aspirin.
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caused by prostatectomy (removal of the
prostate).
Mind-Body Medicine
Meditation
Meditation may reduce stress, ease anxiety,
and allow men with prostate cancer to
regain a sense of self-control.
RESEARCH IN INDIA14,14a
The Advanced Centre for Treatment,
Research and Education in Cancer
(ACTREC) is actively involved in cancer
research.
ACTREC designed to compare Helical
Tomotherapy (HT) based IMRT and
conventional sliding window (SW IMRT) in
patients with high risk prostate cancer.
Complementary plans with HT and SWIMRT
were compared using DVH parameters. The
PTV Prostate was prescribed 74 Gy in 37
fractions and the nodal PTV received 55 Gy
in 37 fractions by simultaneous integrated
boost. Conformity Index, Homogeneity
Index and dose-volume parameters were
compared.
A population based case-control study on
prostate cases was carried out in Delhi to
identify potential risk factors. Cases were
each matched with two controls. Past
smoking and current alcohol consumption
significantly increased the risk of prostate
cancer.
No
statistically
significant
association was found with family history of
cancer or prostate cancer. The risk of
prostate cancer declined with increasing
dietary consumption of tea, citrus fruits and
melon. A statistically significant marginal
increase in the odds ratio was observed
with the consumption of eggs, fish and
sunflower oil. Though an increased risk of
prostate cancer was evident among
vasectomised men, the association was not
statistically significant.
Acupuncture
Acupuncture may provide relief from side
effects of orchiectomy, removal of the
testes. Studies also support using
acupuncture to relieve pain that often
occurs when cancer has spread beyond the
prostate, particularly to the bones. A
National Institutes of Health statement
released in 1997 also supports the use of
acupuncture to reduce nausea from
chemotherapy.
Evidence suggests acupuncture can be a
valuable
therapy
for
cancer-related
symptoms,
particularly
nausea
and
vomiting
that
often
accompanies
chemotherapy treatment. Studies have also
found that acupuncture may help reduce
pain and shortness of breath. Acupressure,
or pressing on rather than needling
acupuncture points, may also help control
breathlessness and is a technique that
patients can learn and then use to treat
themselves.
Massage and Physical Therapy
Studies suggest that massage reduces stress
and boosts immune function, so it may help
relieve anxiety for men being treated for
prostate cancer.
Pelvic floor exercises -- tightening and
releasing muscles that start and stop the
flow of urine -- may help with incontinence
COMMERCIAL ASPECTS OF PROSTATE
CANCER DRUGS15,15a
Four new product launches in prostate
cancer over the next 10 years, including
Medivation’s androgen receptor inhibitor
MDV3100 and Takeda’s 17, 20 lyase
inhibitor TAK-700 will counter generic
erosion. In addition Increasing use of Zytiga
(abiraterone;
Johnson&Johnson)
and
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Jevtana (cabazitaxel;Sanofi) will boost
market value from $1.7bn in 2011 to $4.3bn
by 2020.
The report on prostate drug market from
2005 to 2020 covering 21 major drugs
categorized into four therapies; namely
hormonal
therapy,
chemotherapy,
immunotherapy, and targeted therapy. Out
of 21 drugs, 13 are currently commercially
available in the market and 8 are in
pipeline.
Growing
prostate
cancer
population (25% increase in the incidence
of prostate cancer in mature countries and
40% increase in emerging countries, from
2010 to 2020) is an impetus for the growth
of the market. In 2010, among the mature
markets, U.S. was the major contributor;
accounting for 35% of the total sales of
prostate cancer drugs and amongst the
emerging countries, China contributed to
the share of about 2% of the overall
prostate cancer therapeutics market.
As far as drugs are concerned, Taxotere
accounted for 23% of the total sales of
prostate cancer drugs in 2010. Astrazeneca
PLC is a leading market player with the
share of 30% in the total prostate cancer
therapeutics market, in 2010. However, by
2020, Astrazeneca will lose its market share
by 19%, due to entry of new players such as
Active Biotech, Bristol Myers-Squibb, Teva
Pharmaceuticals Industries Ltd, and
Johnson & Johnson (entered the market in
2011, with its key drug Zytiga).
Players are implementing various growth
strategies in the market to gain a
competitive edge. New products launch,
product
pipelines,
agreements
and
collaborations,
clinical
trials,
and
acquisitions were certain major strategies
adopted by the players from January 2006
to September 2011.



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LHRH analogs - Zoladex, Lupron,
Eligard, Vantas, and Decapeptyl
Antiandrogens - Casodex
Pipeline drugs for hormonal therapy Zytiga, MDV3100, and TAK700
Global prostate cancer chemotherapy
drugs market  Off
patent
drugs
Taxotere,
mitoxantrone, and Emcyt
 Patented drugs – Jevtana.
Global prostate cancer immunotherapy
drugs market Patented drug - Provenge
 Pipeline drug – ipilimumab
Global prostate cancer targeted therapy
drugs market Angiogenesis inhibitor - lanreotide,
TASQ, Zaltrap
 Apoptosis inducing - custirsen sodium
 Signal transduction inhibitor –Sprycel
SUMMARY AND CONCLUSION
The article covers the following
a] Anatomy, Physiology & Pathophysiology
of Prostate gland
b] Types & Pathophysiology of prostate
cancer
c] Awareness & Statistics of prostate cancer
d] Risk factors, Prognosis ,Detection and
Diagnosis, Signs & Symptoms & Treatment
of prostate cancer
e] Drug discovery research & Recently
discovered treatments, New dosage forms,
CAM therapy,&
Commercial aspects of prostate cancer.
Based on the article the following silent
conclusions can be drawn :
Prostate cancer survival tends to be poorer
in developing countries, most likely because
of acombination of late diagnosis and
limited access to standard treatment. A
substantial proportion ofcancer burden can
be prevented by implementing programs,
early detection and treatment, andmajorly
public health check-up camps promoting
investigations.
Clinicians,
health
professionals,and policy makers can play an
active role in the application of such
interventions on a pan-Indialevel.
Identifying risk factors for advanced disease
may help to decrease the rate of poor
Scope of the report
This research report evaluates the prostate
cancer drugs market with respect to the
current and pipeline drugs. The report
analyzes geography; forecasting revenue,
and trends in each of the following
submarkets:
Global prostate cancer
hormonal
therapy drugs market  LHRH antagonists - Firmagon
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Lalla et al.
prostate cancer outcomes and associated
mortality worldwide.
It is recommened that every men beginning
at age 50 should perform yearly PSA
screening and men who are at higher risk of
prostate cancer, including African American
men and men whose father or brother had
prostate cancer, begin screening at age 40
or 45.
Researcher can take their research ahead
through In-Vitro evaluation using cell lines.
9.
REFERENCES
1. American
Cancer
Society,:
http://cajournal.org
and
http://cacancerjournal.org[1a]Natio
nal Collaborating Centre for Cancer,
2008a; Burford et al, 2010; Neal,
2010]
2. Blood borne bio molecular markers
in prostate cancer development and
progression, Robert A. Bok & Eric J.
Small. Nature Reviews Cancer 2,
918-926 (December 2002).
3. Balkrishna B Yeole, Trends in the
Prostate Cancer Incidence in India,
Asian Pacific Journal of Cancer
Prevention, Vol 9, 2008.
4. Bombay Cancer Registry, Indian
Cancer Society, 74, JerbaiWadia
Road, Bhoiwada, Parel, Mumbai –
400 012, Maharashtra.
5. Cancer Statistics, 2010, American
Cancer Society, Available online at:
http://cajournal.org
and
http://cacancerjournal.org
6. American Cancer Society. (Accessed
October
2010)
[http://www.cancer.org/Cancer/Pr
ostateCancer/DetailedGuide/prosta
te-cancer-risk-factors].
7. Murray T; Ward E ; Samuels A;
Tiwari RC; Ghafoor A; Feuer EJ;
Thun MJ... "Cancer statistics, 2005" .
CA Cancer J Clin 55 (1): 10–30.
doi:10.3322/canjclin.55.1.10.
8. Treatments for Localized Prostate
Cancer: Systematic Review to
update the 2002 U.S. Preventive
Services
Task
Force
Recommendation Prepared for
Agency for Healthcare Research and
Quality U.S. Department of Health
and Human Services accessed
10.
11.
12.
13.
198
ISSN: 2249-9504
through
www.ahrq.gov.
[8a]
National cancer institute at NIH
http://www.cancer.gov/cancertopic
s/treatment/prostate/understandin
g-prostatecancertreatment/page3
Prostate Cancer Cell Line Study
Shows Potential New Route to
Cancer Progression, Prostate Cancer
Foundation (PCF) accessed through
http://www.pcf.org. [9a] Ming-Fong
Lin, Technology Transfer Leader For
The University Of Nebraska Medical
Center Prostate Cancer Cellwebsite:
wwww.unemed.com
Prostrate cancer screening CDC
accessed
through
http://www.cdc.gov/cancer/prosta
te/pdf/prosguide.pdf
Support for People with Cancer, a
booklet from the National Cancer
Institute,accessed
through
www.cancer.gov/publications or 1800-4-CANCER
(1-800-4226237).[11a]
National
Cancer
Institute’s Cancer Drug Information
summaries.http://www.cancer.gov/
cancertopics/druginfo/prostatecanc
er.
Xtandi Approved for Advanced
Prostate
Cancer,
through
http://www.dddmag.com/news/20
12/08/xtandi- approved-advancedprostate-cancer[12a] 80 drugs in
development for prostate cancer,
report
PhRMAhttp://prostatecancerinfolin
k.net/2011/04/06/80-drugsindevelopment-for-prostate-cancersays-phrma
[12b]
Rahimi,
Maham,Magnetic Drug Targeting:
Development of A Novel Drug
Delivery System For Prostate Cancer
Therapy available through: websitehttps://dspace.uta.edu/handle/101
06/1031[12c] Gamma-tocotrienol
suppresses prostate cancer cell
proliferation and invasion through
multiple-signalling pathways. Br J
Cancer. 2008 Dec 2;99(11):1832-41
CAM
–REF
Source:
http://www.umm.edu/altmed/artic
les/prostate-cancer000028.htm#ixzz2CwWMG4h0
IJPCBS 2013, 3(1), 185-199
Lalla et al.
14. Murthy V, Mallik S, Master Z,
Sharma PK, Mahantshetty U,
Shrivastava SK,
Does helical
tomotherapy
improve
dose
conformity and normal tissue
sparing compared to conventional
IMRT? A dosimetric comparison in
high risk prostate cancer, Technol
Cancer
Res
Treat.
2011
Apr;10(2):179-85.[14a] 23.Tyagi B,
Manoharan N, Raina VA case control
study on prostate cancer in Delhi,
Dr. BRA Institute Rotary Cancer
Hospital, All India Institue of
Medical Sciences, New Delhi, Asian
ISSN: 2249-9504
Pac J Cancer Prev. 2010;11(2):397401.
15. Market and Product Forecasts:
Prostate
Cancer
http://www.datamonitor.com/store
/Product/market_and_product_fore
casts_prostate_cancer.
[15a]
Prostate
Cancer
Therapeutics
Market (2010-2020) (Opportunity
Analysis, Pipeline Assessment and
Global Market Forecast) reports by
markets and markets through,
http://www.marketsandmarkets.co
m/Market-Reports/prostatecancer-drugs-market-413.html.
199